1. Field of the Invention
This invention relates to a nutritive oil in water emulsion for use in parenteral administration, wherein said nutritive oil is refined or purified soybean oil or sunflower oil. The invention further relates to the purification of nutritive oils used in oil in water emulsions for parenteral feeding, such as soybean and sunflower oil, and in particular, the invention relates to the removal from such oils of undesirable components such as peroxides, pigments and thermal and oxidative decomposition products and polymers. Autoxidation of the purified oil is prevented by adding to the purified oil a tocopherol antioxidant, preferably .gamma.-tocopherol, along with a metal scavenging agent such as ascorbyl palmitate.
2. The Prior Art
Glucose in solution has long been used for the purpose of parenteral nutrition. However, emulsions of certain nutritive oils in water have certain definite advantages over glucose solutions for that purpose. Firstly, oil has a higher caloric content than does glucose. Secondly, since oil is insoluble in water, it does not exert an osmotic effect and thus, can be used in vivo at higher concentrations than can glucose. However, when oil in water emulsions are used for intravenous feeding, there are several distinct problems which must be contended with. Thus, such oil in water emulsions, when injected intravenously, can cause many adverse physiological effects, such as back pain, fever, chills, headache, dizziness, blood pressure fluctuations, liver damage, and the so-called "overloading syndrome", and also, the emulsion may be damaged during storage and transportation under refrigerated temperatures.
A commercial prior art oil-in-water emulsion sold under the name Intralipid is understood to be produced in accordance with the teachings of U.S. Pat. No. 3,169,094 to Wretlind. The literature has reported that abnormalities have been observed in liver function tests during hyperalimentation with Intralipid. Significant eosinophilia has been reported, as well as elevated alkaline phosphatase and brown pigmentation of the reticuloedothelial system of the liver. Swelling of both the mitochondria and endoplasmic reticulum have been noted. Febrile responses, chills, sensation of warmth, shivering, vomiting and pain in chest and back, thrombophelbitis have been observed. [See: A. G. Coran, The Hyperalimination of Infants with a Commercial Fat Emulsion, 110-117. Proceedings of a meeting on Intravenous Feeding held in Vancouver, Canada, January, 1974; Margaret R. Pendray, Peripheral Vein Feeding in Infants: Techniques, Results and Problems, 158-176. Proceedings of a meeting on Intravenous Feeding held in Vancouver, Canada, January, 1974; and Hallberg et al. Fat Emulsion for Complete Intravenous Nutrition. Postgrad. Med. 1967, 42, A-71, 87, 99, 149.]
It is an object of this invention to provide a process for purifying such nutritive oils to remove from the oils those substances which are at least partly responsible for the problems associated with their use in parenteral emulsions. Among these substances are peroxides, pigments, unsaponifiables such as sterols, and thermal and oxidative decomposition products and polymers. It is a further object of the invention to provide a process whereby autoxidation of the purified oils may be retarded.
It has been demonstrated that oils which have been subjected to elevated temperatures in the presence of oxygen from oxidative decomposition products and polymers and that such oxidized oils are toxic. It has been reported that certain fractions of such oxidized oils, and particularly certain of the non-urea-adduct-forming ester fractions are highly toxic when substituted for fresh fats in the diets of test animals. Generally it has been found that the non-urea-adduct-forming materials found in oxidized oils showed a high deviation of organ size (organ enlargement and liver growth depression similar to the liver damage observed in testing Intralipid) in test animals as well as irritation of the digestive tract, cancer and death. [See: Acute Physiological Effects of Feeding Rats. Non-urea-adducting Fatty Acids. Shue, G. M., Douglass, D. C., and Firestone, D. Jour. Nutrition 94, 171-178 (1968); The Effect of Heated Fat on the Carcinogenic Activity of 2-Acetylaminofluorene. Sugai, M., Witting, L. A., Tsuchiyama, H., and Kummerow, F. A. Cancer Res. 22, 510-19 (1962); and The Chemical and Biological Properties of Heated and Oxidized Fats. Artman, N. R. Advances in Lipid Research 7, 245- 330 (1969).]
Many techniques have been proposed in the prior art for purifying nutritive oils for use in oil in water emulsions for parenteral feeding, but none of these techniques involves the use of silicic acid for removing the above-described impurities. [See, e.g., Singleton et al, "A Method For Adsorbent Fractionation of Cottonseed Oil For Experimental Intravenous Fat Emulsions", The Journal of the American Oil Chemists' Society, Vol. 43, pp. 592-595 (1966), which describes, in connection with the preparation of aqueous cottonseed emulsions for parenteral administration, removal of pigments and polar components of cottonseed oil by sequentially treating the oil with bleaching earth and alumina adsorbents.] Similarly U.S. Pat. No. 3,169,094 to Wretlind, describes mild extraction of soybean oil with an organic solvent such as ethanol, ether, or petroleum ether, and deodorization with active carbon and alumina, followed by preparing an aqueous emulsion of the thus treated soybean oil and egg phosphatides, this emulsion being suitable for parenteral administration. As was mentioned above, the commercial version of oil-in-water emulsions produced in accordance with the Wretlind teaching has not been free from problems.
Further, the literature reports that alumina causes decomposition of lipids, and that the treatment of oil with alumina is likely to form various undesirable decomposition products. [See, e.g., "Lipid Chromatographic Analysis", Edited by Guido V. Marinetti, Vol. 1, published by Marcel Dekker, Inc., New York, 1967, page 221, which states:
"Bertstrom (103) and others found, however, that alumina caused alterations in lipid structure during chromatography, namely, alumina partially hydrolyzed glycerides and other fatty acid esters, isomerized mono- and diglycerides, promoted autoxidation and isomerization of double bonds, and caused dehydration of peroxidized lipids."
"Autoxidation of Linoleic Acid" by D. Le Mammick and S. F. Mason, Nature, 156, 717-718 (1945), report the dehydration of peroxides of linoleic acid (a major component of soybean oil and sunflower oil) on treatment with alumina; and "Artifacts Found During Alumina Chromatography", by B. M. Lawrence, J. W. Hogg and S. J. Terhune, Journal of Chromatography 12, 261-262 (1960), reported the dimerization and trimerization of vegetable oil components which were chromatographed with alumina.]